Renal cystic diseases (RCD) include a group of monogenic kidney abnormalities which cause significant morbidity and mortality (Dell, K., et al., Polycystic kidney disease, in Pediatric Nephrology, E. D. Avner, W. E. Harmon, and P. Niaudet, Editors. 2004, Lippincott Williams & Wilkins: Philadelphia. p. 675-699). Histopathologically, renal cysts are fluid filled, epithelia lined, dilated saccular lesions which generally arise from tubular segments. The most common cause of nondysplastic, nonsyndromal multiple renal cysts are autosomal dominant polycystic kidney disease (ADPKD) (MIM 601313 and MIM 173910) (PKD1 and PKD2) and autosomal recessive polycystic kidney disease (ARPKD) (MIM 263200) (PKHD1).
ADPKD is the most common renal monogenic disease with an incidence of about 1 in 500. ADPKD comprises 5-8% of all individuals requiring renal replacement therapy (dialysis and/or kidney transplantation). Approximately 80-85% of ADPKD patients have inherited mutations in the PKD1 gene, located on chromosome 16p13, which encodes for the protein called polycystin-1 (PC-1). The remaining 10-15% of ADPKD cases have mutations in the PKD2 gene located on chromosome 4q21, which encodes for polycystin-2 (PC-2). ADPKD is usually asymptomatic until the middle decades of life because the kidney has reserve function and only 10-15% of health renal mass is needed to sustain life. However, with time renal function in individuals with ADPKD gradually deteriorates as the kidneys become replaced by multitudes of fluid-filled cysts. Eventually the damage to the remaining portions of the kidney becomes so severe that renal replacement therapy becomes necessary. It should also be mentioned that 2-5% of ADPKD patients present with a severe neonatal course and exhibit significant morbidity and mortality in childhood.
ARPKD caused by mutations on PKHD1 is a significant cause of renal and bile duct-related morbidity and mortality in childhood. Estimates of disease prevalence vary widely but an overall frequency of 1 in 20,000 live births and a carrier level up to 1:70 have been recently proposed (Zerres, K., et al., Prenatal diagnosis of autosomal recessive polycystic kidney disease (ARPKD): Molecular genetics, clinical experience, and fetal morphology. Am J Med Genet, 1998. 76: p. 137-144). Liver disease is invariably present in all ARPKD patients (Dell, K., et al., Polycystic kidney disease, in Pediatric Nephrology, E. D. Avner, W. E. Harmon, and P. Niaudet, Editors. 2004, Lippincott Williams & Wilkins: Philadelphia. p. 675-699). The chief pathologic hallmarks of ARPKD associated liver disease are hepatic lesions of biliary dysgenesis due to ductal plate malformation and associated periportal fibrosis resulting in congenital hepatic fibrosis (CHF) and dilatation of intrahepatic bile ducts (Caroli's disease) (Blyth, H. and B. G. Ockenden, J Med Genet, 1971, 8:257-284; Jorgensen, M. J., Acta Pathol Microbiol Scand Suppl, 1977, 257:1-87; Desmet, V. J., Hepatology, 1992, 16:1069-83; Dell, K. and E. Avner. Autosomal recessive polycystic kidney disease. GeneReviews; Genetic Disease Online Reviews at Gene Tests-GeneClinics 2003; Davis, I. D., et al., Pediatr Transplant, 2003, 7:364-9; and Harris, P. C. and S. Rossetti, Mol Genet Metab, 2004, 81:75-85). All patients with CHF have a mutation in the ARPKD gene, PKHD1. The biliary proliferation associated with ARPKD may also lead to cholangiocarcinoma.
Although the mutated genes that cause PKD were identified years ago, the pathway(s) leading from the mutated proteins to the formation of cysts remain unknown and are the subject of intense investigation. Over the years, it has become apparent that the PKD (PKD1, PKD2 and PKHD1) proteins are involved in the transduction of environmental cues into appropriate cellular responses. The expression in of PKD proteins in cilia, basal bodies, intercellular junctions, and at the focal adhesions suggests that there may be common signaling pathways for cyst formation, through the abnormal integration of signal transduction pathways (Wilson P. D., N Engl J Med, 2004, 350:151-64; Nauli S. M. et al., Nat Genet, 2003, 33:129-37).
PKD cystic renal epithelia share common phenotypic abnormalities despite the different genetic mutations that underlie the disease. Numerous animal models as well as in vitro cell culture systems utilizing cells derived from cysts obtained from human and animal models have established that the development of PKD is characterized by a switch from a well-differentiated, nonproliferative, reabsorptive epithelia to a partially dedifferentiated, secretory epithelia characterized by polarization defects and high rates of proliferation and apoptosis (Dell, K., et al., Polycystic kidney disease, in Pediatric Nephrology, E. D. Avner, W. E. Harmon, and P. Niaudet, Editors. 2004, Lippincott Williams & Wilkins: Philadelphia. p. 675-699; Wilson P. D., N Engl J Med, 2004. 350:151-64; Wilson P. D., Int J Biochem Cell Biol, 2004, 36:1868-73; Murcia N. S. et al., Kidney Int, 1999, 55:1187-1197; Harris P. C. and S. Rossetti, Mol Genet Metab, 2004, 81:75-85). It is clear that the development and progressive enlargement of cysts require proliferation of the tubular epithelial cells, transepithelial fluid secretion, and extracellular matrix remodeling (Welling, L. W. and J. J. Grantham, Cystic and developmental diseases of the kidney, in The Kidney, B. M. R. Brenner, F. C., Editor. 1991, WB Saunders: Philadelphia. p. 1657-1694; and Grantham J. J., AM J Kidney Dis, 1996, 28:788-803). Indeed, since the first anatomical studies performed in the 19th century, proliferation has been recognized as the hallmark of cystic epithelia. Cultured epithelial cells from patients or animal models of PKD have consistently demonstrated an increased intrinsic capacity for proliferation and survival (Gabow P. A., N Engl J Med, 1993, 329:332-42; Wilson P. D., N Engl J Med, 2004, 350:151-64; Grantham J. J., AM J Kidney Dis, 1996, 28:788-803; Grantham J. J. et al., Kidney Int, 1987, 31:1145-1152).